title: Nuclear orphan receptor NR4A2 confers chemoresistance and predicts unfavorable prognosis of colorectal carcinoma patients who received postoperative chemotherapy.
abstract: BACKGROUND
  NR4A2, an orphan nuclear receptor essential in neuron generation, has been recently linked to inflammatory and metabolic pathways of colorectal carcinoma (CRC). However, the effects of NR4A2 on chemo-resistance and postoperative prognosis of CRC remain unknown.
  
  
  METHODS
  NR4A2 was transfected into CRC cells to investigate its effects on chemo-resistance to 5-fluorouracil and oxaliplatin and chemotherapeutics-induced apoptosis. We also investigated prostaglandin E2 (PGE2)-induced NR4A2 expression and its effect on chemo-resistance. Tissue microarrays including 51 adenoma, 14 familial adenomatous polyposis with CRC, 17 stage IV CRC with adjacent mucosa and 682 stage I-III CRC specimens were examined immunohistochemically for NR4A2 expression. Median follow-up time for stage I-III CRC patients was 53 months.
  
  
  RESULTS
  Ectopic expression of NR4A2 increased the chemo-resistance, and attenuated the chemotherapeutics-induced apoptosis. Transient treatment of PGE2 significantly up-regulated NR4A2 expression via protein kinase A pathway and increased the chemo-resistance. NR4A2 expression in epithelials consecutively increased from adenoma, adjacent mucosa to CRC (P(trend)<0.001). In multivariate Cox regression analyses, high NR4A2 expression in cancer nuclei (immunoreactive score ≥ 4) significantly predicted a shorter disease-specific survival (DSS) of CRC patients (hazard ratio [HR]=1.88, P=0.024). High NR4A2 expression specifically predicted a shorter DSS of colon cancer patients (dichotomisation, HR=2.55, log-rank test P=0.011), especially for those who received postoperative 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) chemotherapy (3-score range, HR=1.86, log-rank test P=0.020).
  
  
  CONCLUSIONS
  High expression of NR4A2 in CRC cells confers chemo-resistance, attenuates chemotherapeutics-induced apoptosis, and predicts unfavorable prognosis of colon cancer patients, especially for those who received postoperative chemotherapy. NR4A2 may be prognostic and predictive for colon cancer.
authors.affiliation: Department of Epidemiology, Second Military Medical University, Shanghai, China.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Han
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
authors.forename: Liye
authors.initials: L
authors.lastname: Ma
authors.forename: Yibo
authors.initials: Y
authors.lastname: Ding
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Tan
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Tong
authors.initials: T
authors.lastname: Su
authors.forename: Yongwei
authors.initials: Y
authors.lastname: Yu
authors.forename: Wenjun
authors.initials: W
authors.lastname: Chang
authors.forename: Hongwei
authors.initials: H
authors.lastname: Zhang
authors.forename: Chuangang
authors.initials: C
authors.lastname: Fu
authors.forename: Guangwen
authors.initials: G
authors.lastname: Cao
mesh_terms: D000236:Adenoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000601:surgery; D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000601:surgery; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000601:surgery; D015232:Dinoprostone / Q000378:metabolism; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000008:administration & dosage; D045325:HCT116 Cells; D006801:Humans; D007417:Intestinal Polyps / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000601:surgery; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D016016:Proportional Hazards Models; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D009944:Organoplatinum Compounds; D015232:Dinoprostone; D002955:Leucovorin; D005472:Fluorouracil
keywords: Apoptosis; Chemo-resistance; Colorectal carcinoma; Inflammation; NR4A2; Prognosis